Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is an ongoing threat to public health. Globally, approximately two billion people are infected with TB, with nine million newly diagnosed cases of active TB each year causing 1.5 million deaths. Furthermore, mismanagement or inappropriate treatments for TB infections can result in the development of drug resistant TB cases, for which treatments are difficult and expensive. Drug-resistant strains of Mtb are not treatable with frontline therapy and require 12-24 months of complex second and third line antibiotics. In addition, TDR (totally drug resistant) strains exist which cannot be treated with any available antibiotics. The current proposal is designed to develop a novel synergistic combination chemo-immunotherapeutic regimen for the treatment of infections caused by Mtb, including multi-, extremely- and totally- drug resistant strains. An effective treatment that reduces bacterial loads and shortens therapy to less than six months would play an important role in dramatically reducing the impact of this pathogen. This application is an extension of our systematic and methodical approach towards developing vaccines for TB. Over the last twenty years, we have applied this strategy towards developing M72/AS01E (currently in Phase II clinical trials) and ID93/GLA-SE into viable vaccine candidates. At present, to our knowledge, ID93/GLA-SE is the sole TB vaccine candidate that has been tested for prevention and therapy in multiple animal models of TB. Our candidate vaccine has three protective effects: significantly reduces pulmonary bacterial loads, reduces disseminated Mtb infection after aerosol challenge, and post-exposure immunotherapeutic protection. Funding this application will help our continuing efforts to develop an adjuvanted ID93 vaccine towards for future human clinical trials, ultimately resulting in an approved post- exposure TB vaccine.